Methods for the preparation of 1,3-benzodioxole heterocyclic compounds

ABSTRACT

The present invention relates to novel methods for the preparation of 1,3-benzodioxole heterocyclic compounds of formula (I). The compounds are useful as PDE4 inhibitors.

FIELD OF THE INVENTION

The present invention relates to novel methods for the preparation of1,3-benzodioxole heterocyclic compounds. The compounds are useful asPDE4 inhibitors.

BACKGROUND OF THE INVENTION

WO 2011/160632 discloses benzodioxole and benzodioxepene heterocycliccompounds useful as PDE4 inhibitors as well as suitable methods for thepreparation thereof.

WO 2008/104175 discloses benzodioxole and benzodioxepene heterocycliccompounds useful as PDE4 inhibitors as well as suitable methods for thepreparation thereof.

WO 2008/077404 discloses substituted acetophenones useful as PDE4inhibitors as well as suitable methods for the preparation thereof.

WO 2015/197534 discloses methods for the preparation of 1,3-benzodioxoleheterocyclic compounds.

WO 2017/103058 discloses further methods for the preparation of1,3-benzodioxole heterocyclic compounds.

Zafrani et al. Tetrahedron 65, 2009, pp 5278-5283, describes a methodfor the difluoromethylation of phenols and thiophenols.

Sperry et al Org. Process Res. Dev. 15, 2011, pp 721-725, also describesthe difluoromethylation of phenols.

Frey et al. Tetrahedron 2003, 59, pp. 6363-6373 also describes thedemethylation and difluoromethylation of phenols Zhang et al. J. Org.Chem. 2006, 71, 9845-9848 also describes the difluoromethylation ofphenols.

Zheng et al. Chem. Commun. 2007, 5149-5151 also describes thedifluoromethylation of phenols.

In the development of new drug candidates, it is highly desirable tohave access to alternative methods for the preparation of the drugcandidates, as some efficient small-scale synthesis may turn out to bedifficult to up-scale to production scale quantities. Also, small-scalesyntheses may involve reagents and solvents which are not feasible toutilize at a production scale level.

Hence, it is an object of the present invention to provide alternativemethods for the preparation of 1,3-benzodioxole heterocyclic compoundsof the type disclosed in WO 2011/160632, WO 2015/197534 and WO2017/103058, insofar that such alternative methods provide advantageswith respect to one or more features like the number of reactions steps,purity, yield, ease of purification, process economy, availability ofstarting materials and reagents, safety, predictability, etc.

Compared to step (2a) of WO 2017/103058 in step (2a) of the presentinvention, cheaper reagents and more environmentally benign solventswere used and the solution was heated to reflux and stirred until theconversion was ≥98%.

In step (3), when performing the reaction as described in Example 3 ofWO 2017/103058 (Example 5 of the present invention), carbon dioxide isreleased in equimolar amounts to added amount of sodium chlorodifluoroacetate to the reaction. Upon scale-up gas-release and possible pressureincrease in used equipment may turn the procedure into a potentialsafety issue. Therefore, an alternative procedure was developed in orderto be able to control carbon dioxide release over time.

The identification of a by-product in present step (3) has led to newreaction conditions as said by-product is not removed during regularwork-up and isolation of the compound. The use of TFA (trifluoroaceticacid) or MSA (methane sulfonic acid) in a polar solvent, at elevatedtemperature and subsequent removal by treatment with an aqueous base,such as NaOH or KOH during crystallization leads to a purity of >94% ofthe compound.

The identification of an impurity in present step (4) has led to newreaction conditions. The use of a solvent of DMF/tBuOH and a base oftert-BuOK suppressed the formation of impurity to a minimum, whichafforded 70-73% isolated yield. This surpasses the yield of 57% asobtained by the method as in described in WO 2017/103058.

The improved yield, avoidance of potential safety issues, the use ofother reaction conditions and the use of cheaper reagents optimizing theprocess economy of the process of the present invention as compared tothe method as described in WO 2017/103058, WO 2011/160632 and WO2015/197534, are quite surprising.

SUMMARY OF THE INVENTION

It has been found by the present inventors that alternative steps anduse of alternative reagents disclosed herein provides advantages overthe known methods by an improved overall chemical and volumetric yield,avoidance of potential safety issues and reduced cost for theproduction.

Hence, the present invention provides a method for the preparation of1,3-benzodioxole compounds, e.g. a compound of formula (I).

Also within the scope of the invention are intermediates used in theforegoing method for preparing compounds of formula (I).

DETAILED DISCLOSURE OF THE INVENTION

In a first aspect, the present invention relates to a method for thepreparation of a compound of formula (I)

Wherein R₁ is selected from CHF₂ and CF₃, and Q is selected from chloro,bromo and fluoro.

In the compound of formula (I), R₁ is typically CHF₂. Q is typicallyselected from chloro, bromo and fluoro, preferably chloro, where the Q'spreferably are the same. In one embodiment, both Q's are chloro.

Definitions

The term “C₁₋₆-alkyl” is intended to mean a saturated, straight orbranched hydrocarbon chain having from one to six carbon atoms,including methyl, ethyl, propyl, isopropyl, butyl, isobutyl, secondarybutyl, tertiary butyl, pentyl, isopentyl, neopentyl, tertiary pentyl,hexyl and isohexyl. In some embodiments, “C₁₋₆-alkyl” is a C₁₋₄-alkylgroup, e.g. methyl, ethyl, propyl, isopropyl, butyl, isobutyl, secondarybutyl and tertiary butyl. Correspondingly, “C₁₋₃-alkyl” includes methyl,ethyl, propyl and isopropyl.

The term “halogen” is intended to mean one of fluoro, chloro, bromo andiodo. In one embodiment, the term “halogen” designates fluoro or chloro.In another embodiment, the term “halogen” designates chloro.

The term “aryl” is intended to mean a carbocyclic aromatic ring systemderived from an aromatic hydrocarbon by removal of a hydrogen atom. Arylfurthermore includes bi-, tri- and polycyclic ring systems. Examples ofpreferred aryl moieties include phenyl, naphthyl, indenyl, indanyl,fluorenyl, and biphenyl. Preferred “aryl” is phenyl, naphthyl orindanyl, in particular phenyl, unless otherwise stated.

The term “arylalkyl” is intended to mean an aryl radical as definedabove covalently joined to an alkyl group, e.g. benzyl.

Methods of Preparation

It appears that the method provides advantages over the known methods byrelying on cheap starting materials, ease of the production method, andincreasing yields in the reactions.

Step (1)

The method for the preparation of a compound of the formula (I) includesthe formation of a compound of the formula (IV) which is obtained byreacting a compound of formula (II)

wherein R₂ is selected from hydrogen, C₁₋₆-alkyl and arylalkyl, R₂₁ isselected from hydrogen and C(O)R₂₂, and R₂₂ is selected from hydrogenand C₁₋₆-alkyl; with a compound of formula (III)

in the presence of an acid catalyst to form a compound of formula (IV)

wherein R₂ and R₂₁ is as defined above.

The acid catalyst is typically in the form of a clay or a zeolite. Azeolite is typically selected from CBV 720, CBV 760, CBV 780,HSZ-390HUA. A clay is typically selected from Montmorillonite K10, TaikoClassic, Taiko Omega, Actol-10, Actol-20, Actol-20X, Tonsil Supreme 116FF or Tonsil Supreme 115 FF. In one embodiment, a clay is selected fromMontmorillonite K10, Tonsil Supreme 116 FF or Tonsil Supreme 115 FF. Inanother embodiment, the clays is Montmorillonite K10.

The ratio between the zeolite or the clay and compound of formula (II)may have influence on the conversion and filtration-time. Hence, it istypically preferred to have an amount of the zeolite or the clay of10%-w/w to 500%-w/w compared to the compound of formula (II). Inparticular the amount of mineral should be of 25%-w/w to 75%-w/w.preferably in the range 45%-w/w to 55%-w/w.

The reaction is typically conducted in toluene, benzene, 2-Methyl-THF(2-methyl-tetrahydrofuran), EtOAc (ethyl acetate), xylenes, heptane,octane, chlorbenzene and dichlorbenzene. In one embodiment, the solventis toluene or xylenes. In another embodiment, the solvent is toluene.

The reaction is typically conducted at a temperature above 80° C. inorder to promote the reaction. Hence, it is typically preferred that thetemperature is in the range of 80-200° C., such as in the range of100−160° C., especially at 105-115° C. or 135-145° C. In one embodiment,the reaction is performed at reflux of the reaction mixture. Thereaction is typically allowed to proceed for 4-96 hours, such 24-84hours, especially 48-84 hours.

The resulting compound of formula (IV) may be recovered by conventionalmeans, known to those skilled in the art, e.g. by aqueous workupfollowed by extraction and finally precipitation and filtration.

In one embodiment of the invention, the compound of formula (II) iswherein R₂ is selected from hydrogen or methyl and R₂₁ is selected fromhydrogen, COCH₃ or COOH.

In another embodiment, the compound of formula (II) is1-(2,3-dihydroxy-4-methoxyphenyl)ethanone.

In one embodiment of the invention, the compound of formula (III) istetrahydrothiopyran-4-one.

In one embodiment of the invention, the compound of formula (IV) iswherein R₂ is hydrogen, methyl, ethyl, propyl, isopropyl, isobutyl,secondary butyl, tertiary butyl or benzyl, and R₂₁ is selected fromhydrogen, COCH₃ or COOH. In another embodiment the compound of formula(IV) is wherein R₂ is methyl and R₂₁ is COCH₃.

Step (2a)

The compound of the formula (IV)

wherein R₂ and R₂₁ is as defined above, is converted to a compound offormula (VI)

wherein R₂₁ is defined above by deprotecting the phenol moiety.

This may be done by reacting the compound of formula (IV) with anaromatic or aliphatic thiol in combination with a base.

The aromatic thiol may be e.g., but is not limited to, benzenethiol,4-methylbenzene-thiol, 3,5-dimethylbenzenethiol,2,5-dimethylbenzenethiol, 4-isopropylbenzenethiol, or5-tert-butyl-2-methyl-benzenethiol. In one embodiment, the aromaticthiol is 5-tert-butyl-2-methyl-benzenethiol.

The aliphatic thiol may be e.g, but is not limited to, 1-dodecanethiol,1-tetra-decanethiol, 1-hexadecanethiol, or tert-dodecanethiol. In oneembodiment, the aliphatic thiol is 1-dodecanethiol.

The deprotection of the phenol group in step (2a) may be conducted usingvarious solvents, e.g. selected from DMF (N,N-dimethylformamide), NMP(N-methylpyrrolidone), DMSO (dimethyl sulfoxide), methanol, ethanol,1-propanol, 2-propanol and mixtures hereof. In one embodiment, thesolvent is DMF. In another embodiment, the solvent is a mixture of DMFand methanol. In another embodiment the solvent is ethanol. In yetanother embodiment, the solvent is 1-propanol.

The deprotection of the phenol group is performed in the presence of abase, e.g. selected from K₂CO₃, Na₂CO₃, KHCO₃, NaHCO₃, CsCO₃, TEA(triethylamine), a metal hydroxide, e.g. selected from NaOH, KOH andLiOH; and potassium tert-butoxide, tert-BuOLi (lithium tert-butoxide),sodium methoxide, sodium ethoxide, and DIPEA(N,N-diisopropylethylamine). In one embodiment, the base is K₂CO₃. Inanother embodiment, the base is sodium methoxide. In another embodimentthe base is a metal hydroxide, In another embodiment the base is NaOH.

The reaction is typically conducted at a temperature in the range of50-120° C., such as in the range of 70-100° C. The reaction is typicallyallowed to proceed for 2-36 hours, such as 3-24 hours. The reaction istypically allowed to proceed until the conversion is ≥98%.

In a specific embodiment of the present invention a mixture of thecompound of formula (IV), a metal hydroxide, 1-dodecanethiol and analcohol are heated to reflux and stirred. In another specific embodimentof the present invention the metal hydroxide is NaOH and the alcohol isEtOH. In another specific embodiment of the present invention, the metalhydroxid is NaOH and the alcohol is 1-propanol.

The resulting compound of formula (VI) may be recovered by conventionalmeans, known to those skilled in the art, e.g. by aqueous workupfollowed by extraction and finally precipitation and filtration.

In one embodiment of the invention, the compound of formula (VI) iswherein R₂₁ is C(O)R₂₂, and R₂₂ is selected from hydrogen andC₁₋₆-alkyl. In another embodiment the compound of formula (VI) is1-(7-hydroxyspiro[1,3-benzodioxole-2,4′-tetrahydrothiopyran]-4-yl)ethanone.

Step (2b)

In step (2b) the compound of formula (VI) is reacted with aqueous N(Bu)₄⁺OH⁻ to form a compound of formula (VII)

wherein R₂₁ is as defined above.

The mixture is typically heated to a temperature in the range of 20-80°C., such as 55-65° C., until all has dissolved.

The resulting solution is typically washed with a solution of sodiumchloride in water by stirring at a temperature in the range of 20-80°C., such as 55-65° C. for ≥20 min. Subsequently adding a mixture ofwater and sodium chloride followed by cooling of the mixture from ≥35°C. to 0-20° C., e.g. 5° C. over a period of 1-24 hours, such as 1-4hours, causes the TBA (tetrabutylammonium) salt to precipitate. The TBAsalt is isolated e.g. by filtration and dried.

Step (3)

The compound of formula (IX)

wherein R₁ and R₂₁ are as defined above, may be obtained by alkylatingthe resulting compound of formula (VII)

wherein R₂₁ is as defined above, by reacting with ahydrochlorofluorocarbon reagent,

R₁—Cl  (VIII)

wherein R₁ is as defined above.

The alkylation may be conducted using one of various possible reagents,such as various hydrochlorofluorocarbon gases. In one embodiment, thealkylation reaction is conducted using chlorodifluoromethane in anaprotic polar solvent, e.g. selected from DMF (N,N-dimethylformamide),NMP (N-methylpyrolidone), DMI (1,3-dimethyl-2-imidazolidinone), DMSO(dimethyl sulfoxide), EtOAc (ethyl acetate), MeCN (acetonitrile) and THF(tetrahydrofuran), and mixtures hereof. In one preferred embodiment, theaprotic solvent is selected from DMF and NMP. In a particularembodiment, the reaction is conducted using chlorodifluoromethane inDMF.

The reaction is typically conducted at a temperature in the range of40-120° C., such as in the range of 50-70° C. The reaction is typicallyallowed to proceed until ≤4% of the phenol is left in the reactionmixture.

The resulting compound of formula (IX) may be recovered by conventionalmeans, known to those skilled in the art, e.g. by aqueous workupfollowed by precipitation and subsequently filtration.

In one embodiment of the invention, the compound of the formula (IX) is1-[7-(difluoromethoxy)spiro[1,3-benzodioxole-2,4′-tetrahydrothiopyran]-4-yl]ethanone.

Alternative Step (2b+3)

Alternatively, the compound of formula (IX),

wherein R₁ and R₂₁ are as defined above, may be obtained from thecompound of formula (VI),

wherein R₂₁ is defined above, without forming the intermediate salt ofthe formula (VII), by using a difluoromethylating reagent in a polarsolvent in the presence of a base.

The difluoromethylating reagent is selected from e.g., but not limitedto, sodium chlorodifluoroacetate, sodium bromodifluoroacetate, diethylbromodifluoromethylphosphonate, chlorodifluoromethyl phenyl sulfone, and2-chloro-2,2-difluoroaceto-phenone. Those skilled in the art can easilychoose other suitable analogous of the mentioned difluoromethylatingreagent. In one embodiment, the difluoromethylating reagent is sodiumchlorodifluoroacetate. In another embodiment, the difluoromethylatingreagent is diethyl bromodifluoromethylphosphonate.

The reaction is performed in a solvent selected from e.g. DMF(N,N-dimethylformamide), NMP (N-methylpyrolidone), DMI(1,3-dimethyl-2-imidazolidinone), DMSO (dimethyl sulfoxide), EtOAc(ethyl acetate), MeCN (acetonitrile), THF (tetrahydrofuran), ethanol,methanol, water, and mixtures hereof. In one embodiment, the solvent isa mixture of water and DMF. In another embodiment, the solvent is amixture of water and acetonitrile.

The reaction is performed in the presence of a base selected from e.g.K₂CO₃, Na₂CO₃, KHCO₃, NaHCO₃, CsCO₃, TEA (triethylamine), tert-BuOLi(lithium tert-butoxide), sodium methoxide, sodium ethoxide, DIPEA(N,N-diisopropylethylamine), KOH, NaOH, LiOH. In one embodiment, thebase is K₂CO₃. In another embodiment, the base is NaOH.

The reaction is typically conducted at a temperature in the range of0-120° C., such as 6-115° C. In one embodiment, the reaction isperformed at 6-20° C. using diethyl bromodifluoromethylphosphonate asdifluoromethylating reagent. In another embodiment, the reaction isperformed at ambient temperature to 111° C. using sodiumchlorodifluoroacetate as difluoromethylating reagent.

When performing the above reaction as described in present Example 5,carbon dioxide is released in equimolar amounts to added amount ofsodium chlorodifluoro acetate to the reaction. Upon scale-up gas releaseand possible pressure increase in used equipment may turn the procedureinto a potential safety issue.

Therefore, an alternative procedure was developed in order to be able tocontrol carbon dioxide release over time from the reaction.

Alternative Step (2b+3′)

Alternatively, the compound of formula (IX),

wherein R₁ and R₂₁ are as defined above, may be obtained from thecompound of formula (VI),

wherein R₂₁ is defined above, by addition of a solution of the compoundof formula (VI) and sodium chlorodifluoro acetate in DMF to a pre-heatedmixture of DMF, water and potassium carbonate over an extended period oftime; as described in present Example 8.

In one embodiment of the invention, the compound of the formula (IX) is1-[7-(difluoromethoxy)spiro[1,3-benzodioxole-2,4′-tetrahydrothiopyran]-4-yl]ethanone.

The resulting compound of formula (IX), wherein R₁ and R₂₁ are asdefined above, may be recovered by conventional means, known to thoseskilled in the art, e.g. by aqueous workup followed by precipitation andsubsequently filtration.

During the reaction of forming the compound of formula (IX), aby-product of formula (IXb) is formed in considerable amounts.

The by-product is hydrolyzed to the corresponding phenol which compoundis then purged from the product by treatment with TFA or MSA in a polarsolvent, such as DMF, at elevated temperature, and subsequent removal bytreatment with an aqueous base such as NaOH or KOH duringcrystallization of the compound of formula (IX).

Step (4)

In step (4), the compound of formula (IX) is reacted with a pyridinecompound of formula (X)

wherein Q is as defined above and Q_(X) is selected from chloro, bromo,fluoro and iodo to form a compound of formula (XI)

wherein R₁ and Q are as defined above.

The pyridine coupling in step (4), is typically conducted in an polarsolvent, e.g. selected from DMF (N,N-dimethylformamide), NMP(N-methylpyrrolidone), DMI (1,3-dimethyl-2-imidazolidinone), DMSO(dimethyl sulfoxide), MeCN (acetonitrile), THF (tetrahydrofuran), tBuOH(tert-butylalcohol) and mixtures hereof, in the presence of a base, e.g.selected from tert-BuOK (potassium tert-butoxide), tert-BuOLi (lithiumtert-butoxide), tert-BuONa (sodium tert-butoxide), sodium or potassiummethoxide, sodium or potassium ethoxide, K₂CO₃, Na₂CO₃, KHCO₃, NaHCO₃,Et₃N (triethylamine) and DIPEA (N,N-diisopropylethylamine). In oneembodiment, the solvent is DMF and the base is tert-BuOK.

Usually two equivalents or more of the base is used relative to thecompound of the formula (IX), such as where the molar ratio(base)/(formula IX) is from 5:1 to 2:1, e.g. from 3:1 to 2:1, especiallyfrom 2.4:1 to 2.7:1.

The reaction in step (4) is typically conducted at a temperature of0-40° C., such as 5-25° C.

In one embodiment of the invention, the compound of formula (X) is3,4,5-trichloropyridine.

In one embodiment of the invention, the compound of formula (XI) is2-(3,5-dichloro-4-pyridyl)-1-[7-(difluoromethoxy)spiro[1,3-benzodioxole-2,4′-tetrahydrothiopyran]-4-yl]ethanone.

During the reaction, an impurity of formula (XII) is formed inconsiderable amounts.

This impurity is purged from the product by crystallising the productfrom a solvent selected from e.g. dimethylformamide (DMF), ethanol,methanol, ethyl acetate, hexane, heptane, and mixtures thereof. In oneembodiment of the invention, the solvent is a mixture of ethyl acetateand ethanol.

During a detailed study of the reaction, an impurity of formula (XIIb)has been isolated in a significant amount.

The identification of impurity (XIIb) has led to new reactionconditions, as described below.

In Step (4), the solvent used was a DMF/tBuOH 30/70 v/v mixture and thebase was tert-BuOK. Under these conditions the formation of impurity(XIIb) was suppressed to a minimum, while the reaction durationtypically was 3-24 hours. The temperature range was 20-30° C. The newprocess afforded 70-73% isolated yield, surpassing the yield of 57% asobtained by the method as described in WO 2017/103058.

Step (5)

The oxidation of the resulting compound of formula (XI) is conducted toform the compound of formula (I)

wherein R₁ and Q are as defined above, by reacting said compound offormula (XI) with an oxidation reagent.

The oxidation reagent is typically selected from PAA (peracetic acid) inAcOH (acetic acid), and H₂O₂ (aq) in formic acid or acetic acid. In onepreferred embodiment, the oxidation reagent is PAA in AcOH. In oneembodiment the amount of PAA used relative to (XI) (molar ratio) istypically 3 to 6, such as 3.8 to 4.2. The oxidation reagent is typicallyslowly added over a period of 1-8 hours, such as 3-5 hours, keeping thetemperature in the range of 15-100° C., such as in the range of 15-50°C., especially in the range of 15-40° C.

The reaction is typically conducted at a temperature in the range of30-70° C., such as 40-60° C., especially 48-55° C., and stirred for 3-48hours, such as 16-24 hours.

Purification of the Compound of Formula (I)

The resulting crude product of formula (I) may advantageously bepurified by crystallization, precipitation, chromatography or the like.

In one embodiment the resulting crude product of formula (I) iscrystallized from a mixture of water and EtOH (ethanol), and isolated byfiltration and dried.

In another embodiment, the first crystallization from water is skipped,and the compound of formula (I) is crystallized (form E) directly fromthe concentrated reaction mixture.

The crystalline form E of2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-[7-(difluoromethoxy)-1′,1′-dioxo-spiro[1,3-benzodioxole-2,4′-thiane]-4-yl]ethenonehas an X-ray powder diffraction pattern as appears from Graph 1.

Experimentals Methods and Reagents

All chemicals and reagents used were available from commercial sources.

¹H nuclear magnetic resonance (NMR) spectra were recorded at theindicated magnetic field and chemical shift values (δ, in ppm) arequoted in the specified solvent relative to tetramethylsilane (δ=0.00).

HPLC: Column: Aeris Peptide 3.6 μm XB-C18, 100×4.6 mm, the eluent was agradient of A: 10% MeCN; 90% H2O; 0.1% TFA and B: 90% MeCN; 10% H2O;0.1% TFA, column temperature: 35° C., UV detection at 220 nm, flow rate:1.5 mL/min. The following gradients of the eluents were used:

Gradient Steps 2a, 2b, 3, and 5

Time (min) % A % B 0 85 15 8 20 80 10 20 80 10 85 15 12.2 85 15

Gradient Step 4

Time (min) % A % B 0 75 25 5 20 80 12.2 20 80 12.2 75 25 13.2 75 25

Example 1 Step (1): Preparation of1-(7-methoxyspiro[1,3-benzodioxole-2,4′-tetrahydrothiopyran]-4-yl)ethanone

A reactor was charged with 1-(2,3-dihydroxy-4-methoxy-phenyl)ethanone(60.0 kg, 329 mol), tetrahydrothiopyran-4-one (37.2 kg, 320 mol),Montmorillonite K 10 (30.0 kg), and toluene (720.0 L). The mixture wasstirred with heating to reflux, applying a jacket temperature of140-150° C. for 84 hours. The mixture was cooled to 86-90° C. andfiltered through a bed of filter aid. The reactor was rinsed with hot(86-90° C.) toluene (120 L), and the hot toluene was then used to washthe bed of filter aid. The rinse of the reactor and the following washof the bed of filter aid was repeated two times with hot toluene (120L), and once with hot (70° C.) ethyl acetate (60 L). All the toluene andethyl acetate filtrates were combined and cooled to 2-6° C. overapproximately 6 hours. The mixture was stirred at 2-6° C. forapproximately half an hour.

Unconverted starting material was collected by filtration, and dried invacuo at 43-47° C. Yield 32.0 kg.

The filtrate from the isolation of unconverted starting material wascooled to 10-16° C. with stirring, and a mixture of sodium hydroxide(26.40 kg) and water (162.0 L) was added at 10-16° C. The reactionmixture was then stirred for approximately half an hour at 10-16° C.,then the agitation was stopped, and the phases were allowed to settle.The lower aqueous phase was discarded, and then a mixture of sodiumhydroxide (26.40 kg) and water (162 L) was added with stirring at 10-16°C. The mixture was stirred for approximately one hour, then agitationwas stopped, and the phases were allowed to settle. The lower aqueousphase was discarded and the organic phase was transferred to acontainer. The reactor was rinsed with toluene, and then the organicphase was transferred back to the reactor through a Cartridge filter.

The solution was concentrated as much as possible in vacuo applying atemperature of 70° C. Ethanol (90.0 L) was added, and the mixture washeated to 47-53° C., and stirred at that temperature for 10-15 minutes.Then the mixture was concentrated as much as possible in vacuo at atemperature 55° C. Ethanol (120.0 L) was added to the reactor, themixture was heated to reflux with stirring, and water (90.0 L) was addedwith heating, keeping the mixture at reflux. The mixture was cooled to2-8° C. over approximately 10 hours and stirred at that temperature forapproximately half an hour.

The product was isolated by filtration, washed with a mixture of ethanol(30.0 L) and water (22.8 L), and dried in vacuo at 43-47° C. Yield 21.80kg (24% but 51% if corrected for recovered starting material). ¹H NMR(600 MHz, DMSO-d6) δ 7.30 (d, J=9.0 Hz, 1H), 6.75 (d, J=9.0 Hz, 1H),3.88 (s, 3H), 2.91-2.84 (m, 2H), 2.84-2.77 (m, 2H), 2.49 (s, 3H),2.30-2.22 (m, 2H), 2.22-2.12 (m, 2H).

Step (1) was repeated as necessary in order to produce the needed amountof1-(7-methoxyspiro[1,3-benzodioxole-2,4′-tetrahydrothiopyran]-4-yl)ethanone.

Other catalysts was used in the process; the table below summarizes theyield of the reaction and the amount of recovered starting material whenthe above procedure was performed with a series of clays and zeolites.

Input Recovered starting Yield SM Catalyst Supplier material % %HSZ-390HUA Tosoh Corp. 20 g 15 63 CBV 720 Zeolyst Int. 20 g 17 56 CBV760 Zeolyst Int. 150 g 18 57 CBV 780 Zeolyst Int. 50 g 16 48 TaikoClassic Taiko Clay Group 10 g 9 61 Taiko Omega Taiko Clay Group 10 g 1863 Actol-10 Ashapura 20 20 55 Perfoclay ltd Actol-20 Ashapura 20 g 20 56Perfoclay ltd Actol-20X Ashapura 150 g 20 57 Perfoclay ltd TonsilSupreme Clariant Produkte 150 g 41 33 116 FF GmbH Tonsil SupremeClariant Produkte 100 g 31 41 115 FF GmbH

Step (2a): Preparation of1-(7-hydroxyspiro[1,3-benzodioxole-2,4′-tetrahydrothiopyran]-4-yl)ethanone

A reactor was charged with1-(7-methoxyspiro[1,3-benzodioxole-2,4′-tetrahydrothiopyran]-4-yl)ethanone(26.0 kg, 92.7 mol), potassium carbonate (14 kg, 101 mol),dimethylformamide (104 L), and 5-tert-butyl-2-methyl-benzenethiol (26.8kg, 149 mol). The mixture was heated with stirring to 85-92° C. until aconversion of ≥98% was achieved, as indicated by HPLC. The mixture wasthen cooled to 25° C., added water (104 L) and sodium hydroxide (28% inwater, 21.4 kg), and stirred for ≥10 minutes. If pH of the mixture wasbelow 12, more sodium hydroxide (28% in water) was added. Then toluene(65 L) was added, and stirring was continued for ≥15 minutes. Theagitation was stopped, and the phases were allowed to settle. The phaseswere separated and the organic phase was discarded. The two loweraqueous phases were stirred with toluene (65 L) and the mixture wasstirred for ≥15 minutes. The agitation was stopped, allowing the phasesto settle. The phases were separated and the organic phase wasdiscarded. The two aqueous phases were returned to the reactor andhydrochloric acid (18% in water, 67.6 kg) was added slowly with stirringin order to control the gas evolution. The resulting mixture was stirredfor ≥10 minutes. More hydrochloric acid (18% in water, 10.2 kg) wasadded in order to achieve pH

The temperature of the mixture was adjusted to 35-45° C. and kept thereduring the following extractions. Ethyl acetate (156 L) was added andthe mixture was stirred for ≥30 minutes. The stirring was stopped, andthe phases were allowed to settle. The phases were separated. Theaqueous phase was stirred with ethyl acetate (78 L) for ≥30 minutes. Theagitation was stopped, and the phases were allowed to settle. Theaqueous phases was discarded. The two ethyl acetate phases were combinedin the reactor and stirred with water (78 L) for ≥15 minutes. Thestirring was stopped, and the phases were allowed to separate. Theaqueous phase was discarded.

The organic phases were concentrated as much as possible with a jackettemperature of 50-60° C. and applying a vacuum. Then heptane (39 L) wasadded, and the resulting mixture was cooled to ≤5° C. with a rate of≤10° C./h, and kept at that temperature for ≥3 hours. The title compoundwas isolated by filtration, washed with a cold (≤5° C.) mixture of ethylacetate (10 L) and heptane (10 L), and dried in vacuo at 40-50° C. Yield19.75 kg (80%). ¹H NMR (600 MHz, DMSO-d6) b 10.51 (s, 1H), 7.18 (d,J=9.0 Hz, 1H), 6.50 (d, J=9.0 Hz, 1H), 2.93-2.85 (m, 2H), 2.84-2.78 (m,2H), 2.46 (s, 3H), 2.31-2.23 (m, 2H), 2.20-2.11 (m, 2H).

Step (2b): Tetrabutylammonium7-acetylspiro[1,3-benzodioxole-2,4′-tetrahydrothiopyran]-4-olate

1-(7-hydroxyspiro[1,3-benzodioxole-2,4′-tetrahydrothiopyran]-4-yl)ethanone(19.75 kg, 74.16 mol) was charged to a suitable reactor followed bytetrabutylammonium hydroxide (40% solution in water, 53.0 kg, 81.7 mol).The jacket temperature was set to 60° C. and the mixture was stirreduntil all had dissolved. A saturated solution of sodium chloride inwater (59.2 kg) was added and stirring was continued with a jackettemperature of 60° C. for ≥20 minutes. The agitation was stopped,allowing the phases to separate. The lower aqueous phase was discarded.The mixture in the reactor was stirred again with a jacket temperatureof 60° C. A saturated solution of sodium chloride in water (29.6 kg) andthen water (25 L) were added. The mixture was stirred for 15 minutes ata temperature ≥35° C. in the mixture. The mixture was cooled to 0-5° C.at a rate of approximately 20° C./hr, the mixture was seeded at 40° C.and again at 35° C. The mixture was stirred at 0-5° C. for ≥2 hours, andthen the title compound was isolated by filtration and dried in vacuo at40-50° C. Yield 32.9 kg (87%). ¹H NMR (600 MHz, DMSO-d6) δ 6.94 (d,J=9.1 Hz, 1H), 5.74 (d, J=9.1 Hz, 1H), 3.23-3.07 (m, 8H), 2.87-2.72 (m,4H), 2.25 (s, 3H), 2.16-2.07 (m, 2H), 2.06-1.96 (m, 2H), 1.62-1.51 (m,8H), 1.30 (h, J=7.4 Hz, 8H), 0.93 (t, J=7.4 Hz, 12H).

Step (3):1-[7-(difluoromethoxy)spiro[1,3-benzodioxole-2,4′-tetrahydrothiopyran]-4-yl]ethanone

Tetrabutylammonium7-acetylspiro[1,3-benzodioxole-2,4′-tetrahydrothiopyran]-4-olate (32.93kg, 64.85 mol) and dimethylformamide (198 L) were added to a reactor.The mixture was stirred until all had dissolved. Chlorodifluoromethane(39.5 kg, 457 mol) was added to the solution via a dip pipe on thereactor. The reaction mixture was heated to 50-55° C. and stirred until≤4% of the starting material was left as indicated by HPLC. The reactionmixture was cooled to 20-25° C. and transferred to a container via afilter. The reactor and the solid in the filter were washed withdimethylformamide (10 L) which was added to the container as well.

Water (198 L) and sodium hydroxide (28% in water, 11.0 kg) were chargedto the reactor and heated to 45-55° C. The reaction mixture in thecontainer was added slowly to the reactor with stirring, keeping thetemperature at 45-55° C. The mixture was then cooled to 5-10° C. andstirred at that temperature for ≥2 hours. The product was isolated byfiltration, washed with water (82 L), and dried in vacuo at 45-55° C.with a bleed of nitrogen. Yield 19.08 kg (94%). ¹H NMR (600 MHz,DMSO-d6) δ 7.34 (t, J=73.1 Hz, 1H), 7.32 (d, J=9.1 Hz, 1H), 6.86 (d,J=9.1 Hz, 1H), 2.92-2.80 (m, 4H), 2.54 (s, 3H), 2.34-2.27 (m, 2H),2.27-2.19 (m, 2H).

Step (4)2-(3,5-dichloro-4-pyridyl)-1-[7-(difluoromethoxy)spiro[1,3-benzodioxole-2,4′-tetrahydrothiopyran]-4-yl]ethanone

Dimethyl formamide (96 L) was charged to a suitable reactor followed byaddition of potassium tert-butoxide (17.60 kg, 156.8 mol). Transfer ofpotassium tert-butoxide was ensured with a rinse of dimethyl formamide(3 L), and the mixture was stirred until potassium tert-butoxide haddissolved. The solution was transferred from the reactor to a container,the reactor was rinsed with dimethyl formamide (6 L), which wastransferred to the container as well.

The reactor was charged with1-[7-(difluoromethoxy)spiro[1,3-benzodioxole-2,4′-tetrahydrothiopyran]-4-yl]ethanone(19.08 kg, 60.32 mol), 3,4,5-trichloropyridine (14.30 kg, 78.38 mol),and dimethylformamide (96 L). The mixture was stirred and cooled to10-15° C., and then the solution of potassium tert-butoxide indimethylformamide was added slowly, keeping the temperature of thereaction mixture at 5-25° C. The transfer of the potassium tert-butoxidesolution was ensured with a rinse of dimethyl formamide (6 L). Themixture was heated to 20-25° C. and stirred until the conversion was≥98% as indicated by HPLC.

Water (96 L) was added slowly with cooling to the reaction mixturekeeping the temperature between 20-30° C. This was followed by theaddition of saturated sodium chloride in water (115.2 kg) and ethylacetate (134 L). The mixture was stirred for 20-60 minutes and then theagitation was stopped, allowing the phases to settle. The phases wereseparated, and the aqueous phase was returned to the reactor. Ethylacetate (96 L) was added, and the mixture was stirred for 20-60 minutes.The agitation was stopped, allowing the phases to settle. The phaseswere separated. The organic phases were combined in the reactor andstirred with water (48 L) and saturated sodium chloride in water (57.8kg) for ≥20 minutes. The agitation was stopped allowing the phases tosettle. The lower aqueous phase was discarded, and water (48 L) andsaturated sodium chloride (57.6 kg) were added. The mixture was agitatedfor 20-60 minutes, and then the agitation was stopped, allowing thephases to settle. The lower aqueous phase was discarded, and water (84L) and sodium hydroxide (28% in water, 14.0 kg) were added. The mixturewas stirred for 20-60 minutes and then the agitation was stopped,allowing the phases to settle. The lower aqueous phase was discarded.

The organic phase in the reactor was concentrated by use of vacuum andheating with a jacket temperature of 50-65° C. to a residual volume ofapproximately 40 L. Ethanol (57 L) was charged to the reactor, and themixture was heated to reflux until a clear solution was obtained. Themixture was cooled to 5° C. over ≥5 hours and stirred at thattemperature for ≥3 hours. The product was isolated by filtration,transfer was ensured with a rinse of ethanol (10 L). The product waswashed with cold (5°) ethanol (48 L) and dried in vacuo at 45-55° C.Yield 15.57 kg (56%). ¹H NMR (600 MHz, Chloroform-d) δ 8.52 (s, 2H),7.46 (d, J=8.9 Hz, 1H), 6.80 (d, J=8.9 Hz, 1H), 6.73 (t, J=73.3 Hz, 1H),4.59 (s, 2H), 3.01-2.85 (m, 4H), 2.47-2.30 (m, 4H). HPLC: Purity: 97.8%.

Step (5):2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-[7-(difluoromethoxy)-1′,1′-dioxo-spiro[1,3-benzodioxole-2,4′-thiane]-4-yl]ethanone

A reactor was charged with2-(3,5-dichloro-4-pyridyl)-1-[7-(difluoromethoxy)-spiro[1,3-benzodioxole-2,4′-tetrahydrothiopyran]-4-yl]ethanone(15.6 kg, 33.7 mol) and glacial acetic acid (78.0 kg) and the mixturewas cooled to 13-20° C. Per acetic acid (36-40% in acetic acid, 6.52 kg,32.6 mol) was added slowly keeping the temperature below 40° C. Themixture was heated to 40-50° C. and stirred for 10-25 minutes. Themixture was cooled to 13-20° C. and a second portion of per acetic acid(36-40% in acetic acid, 6.51 kg, 32.5 mol) was added slowly keeping thetemperature below 40° C. The mixture was heated to 40-50° C. and stirredfor 10-25 minutes. The mixture was cooled to 20-30° C. and a thirdportion of per acetic acid (36-40% in acetic acid, 14.3 kg, 71.5 mol)was added slowly. The mixture was heated to 48-55° C. and stirred untilthe conversion was 98.5%. The mixture was cooled to 20-25° C. and amixture of sodium metabisulphite (7.21 kg, 37.9 mol) and water (46 L)was added slowly keeping the temperature below 35° C.

2-propanol (78 L) was added and the mixture was heated to 60-65° C. andfiltered hot. The reactor was cleaned and the filtrated reaction mixturewas returned to the reactor. The mixture was heated to 60-65° C. andwater (234 L) was added slowly keeping the temperature above 55° C. Themixture was stirred for 30-60 minutes at 60-65° C., cooled slowly to 5°C. over 12 hours, and stirred at 0-10° C. for ≥2 hours. The raw productwas isolated by filtration, washed with water (27 L), and dried in vacuofor approximately two hours.

The solid was returned to the reactor and heated to reflux with ethanol(390 L). The mixture was then cooled to 68-72° C. and seeded. Themixture was cooled to 5° C. over 13 hours and stirred at 0-10° C. for ≥2hours. The product was isolated by filtration, washed with a cold (0-10°C.) mixture of water (4 L) and ethanol (39 l), and dried in vacuo at45-55° C. with a bleed of nitrogen. Yield 14.6 kg (85%). 1H NMR (600MHz, Chloroform-d) δ 8.23 (s, 2H), 7.52 (d, J=9.1 Hz, 1H), 6.90 (d,J=9.1 Hz, 1H), 6.71 (t, J=72.3 Hz, 1H), 4.49 (s, 2H), 3.47-3.38 (m, 2H),3.33-3.24 (m, 2H), 2.83-2.75 (m, 2H), 2.75-2.68 (m 2H). HPLC: purity98.6%.

Example 21-(7-hydroxyspiro[1,3-benzodioxole-2,4′-tetrahydrothiopyran]-4-yl)ethanone

Sodium methoxide in methanol (30%, 64.2 mL, 0.34 mol) was added to asolution of1-(7-methoxyspiro[1,3-benzodioxole-2,4′-tetrahydrothiopyran]-4-yl)ethanone(50.0 g, 0.178 mol) in dimethylformamide (250 mL) at 25-30° C. Then1-dodecane-thiol (64.88 mL, 0.271 mol) was added at 25-30° C. and themixture was heated to 95-100° C. for three hours. The reaction mixturewas cooled to 25-30° C. and sodium hydroxide (28% in water, 50 mL) andwater (250 mL) were added. The resulting mixture was stirred for half anhour and then the mixture was extracted with toluene (250 mL) threetimes. The aqueous solution was acidified with hydrochloric acid (6M) toapproximately pH 6 and extracted with ethyl acetate (250 mL) four times.The ethyl acetate extracts were combined, washed with brine (250 mL)four times, and concentrated to approximately 50 mL using a rotaryevaporator. Heptane (300 mL) was added and the mixture was stirred forone hour at ambient temperature. The product was isolated by filtration,washed with heptane (100 mL), and dried. Yield 44.3 g (93%). NMRcomplied with NMR of the product from step (2a) in Example 1.

Example 31-(7-hydroxyspiro[1,3-benzodioxole-2,4′-tetrahydrothiopyran]-4-yl)ethanone

Sodium hydroxide (31.4 g, 0.785 mol) was added to a solution of1-(7-methoxyspiro[1,3-benzodioxole-2,4′-tetrahydrothiopyran]-4-yl)ethanone(15.0 g, 53.5 mmol) in EtOH (500 mL) at 25-30° C. Then 1-dodecane-thiol(197 mL, 0.87 mol) was added at 25-30° C. and the mixture was heated toreflux and stirred for twenty four hours. From the reaction mixture wasthen removed 300 ml solvent under vacuum. To the remaining slurry wasthen added water (500 ml). The obtained solution was then extracted withtoluene (500 ml). The organic phase was then discarded and remainingaqueous phase was acidified with hydrochloric acid (1M) to approximatelypH 3-5. The product was isolated by filtration, washed with water (2×100mL), and dried under vacuum at 60° C. Yield 93.0 g (98%). NMR compliedwith NMR of the product from step (2a) in Example 1

Example 41-(7-hydroxyspiro[1,3-benzodioxole-2,4′-tetrahydrothiopyran]-4-yl)ethanone

Sodium hydroxide (4.7 g, 117.7 mmol) was added to a solution of1-(7-methoxyspiro[1,3-benzodioxole-2,4′-tetrahydrothiopyran]-4-yl)ethanone(100.0 g, 0.357 mol) in 1-propanol (75 mL) at 25-30° C. Then1-dodecane-thiol (29.5 mL, 123.1 mmol) was added at 25-30° C. and themixture was heated to reflux and stirred for six hours. The reactionmixture was cooled to 25° C. Water (75 ml) was then added to thereaction mixture and then extracted twice with toluene (2×75 ml). Theorganic phases were then discarded and the remaining aqueous phase wasacidified with hydrochloric acid (1M) to approximately pH 3-5. Theproduct was isolated by filtration, washed with water (2×50 mL), anddried under vacuum at 60° C. Yield 11.3 g (79%). NMR complied with NMRof the product from step (2a) in Example 1

Example 51-[7-(difluoromethoxy)spiro[1,3-benzodioxole-2,4′-tetrahydrothiopyran]-4-yl]-ethanone

A mixture of1-(7-hydroxyspiro[1,3-benzodioxole-2,4′-tetrahydrothiopyran]-4-yl)ethanone(221.6 g, 0.8322 mol), potassium carbonate (161.3 g, 1.167 mol), sodiumchlorodifluoroacetate (292.0 g, 1.915 mol), dimethylformamide (1.50 L),and water (500 mL) was stirred in a 5 liter reaction flask and heatedslowly to 106-111° C., gas evolution was observed from approximately 78°C. The reaction mixture was stirred at 106-111° C. until the gasevolution had ceased, approximately two hours. The mixture was cooledwith an ice-water bath, and water (1.00 L) was added slowly at 30-32° C.The resulting suspension was cooled further to 6° C. under stirring. Theraw product was isolated by filtration and washed with water.

The wet raw product was stirred with ethyl acetate (1.66 L) and sodiumhydroxide (1 M, 560 mL) for approximately 20 minutes, and then thephases was separated in a separatory funnel. The lower aqueous phase wasdiscarded and the organic phase was washed twice with water (two times560 mL). The organic phase was concentrated using a rotary evaporator(in vacuo with 60° C. in the water bath) to approximately 450 mL. Ethylacetate (1.56 L) was added, and the mixture was concentrated again usinga rotary evaporator as above to approximately 450 mL. Ethyl acetate(1.44 L) was added, and the unclear solution was filtered, transferringand washing with a fresh portion of ethyl acetate (100 mL). The combinedfiltrates were filtered through a plug of activated carbon (6.0 g),transferring and washing with ethyl acetate (200 mL). The combinedfiltrates were concentrated on a rotary evaporator as above toapproximately 450 mL. The resulting hot solution (approximately 60° C.)was stirred at ambient temperature while heptane (2.00 L) was addedslowly over approximately half an hour. The suspension was stirred atambient temperature for 14 hours.

The mixture was stirred in an ice-water bath for approximately 2.5hours, the temperature of the mixture was then 4° C. The product wasisolated by filtration, washed with an ice-cold mixture of heptane andethyl acetate (10:1, 200 mL), and dried in vacuo at 50° C. with a bleedof air. Yield 201 g (76%). NMR complied with NMR of the product fromstep 3 in example 1.

Example 61-[7-(difluoromethoxy)spiro[1,3-benzodioxole-2,4′-tetrahydrothiopyran]-4-yl]-ethanone

Sodium hydroxide (6.16 g, 154 mmol) was dissolved in water (40 mL) andthe solution was stirred with cooling in an ice-water bath.1-(7-hydroxyspiro[1,3-benzodioxole-2,4′-tetrahydrothiopyran]-4-yl)ethanone(2.00 g, 7.51 mmol) and acetonitril (20 mL) were added, and stirringwith cooling was continued. Diethyl bromodifluoromethylphosphonate (2.67mL, 15.0 mmol) was added in one portion at 6° C., and stirring withcooling was continued for approximately 20 minutes. The cooling bath wasremoved, and the mixture was stirred for approximately 21 hours atambient temperature.

The phases were separated using a separatory funnel, and the water phasewas extracted with ethyl acetate (20 mL). The combined organic phaseswere washed with water (20 mL) and then with brine (20 mL). The organicphase was concentrated to dryness using a rotary evaporator. Ethylacetate (20 mL) was added to the residue, and the mixture wasconcentrated to dryness once again using the rotary evaporator.

The residue was dissolved in ethyl acetate (30 mL) and filtered,transferring and washing with ethyl acetate (20 mL). The combinedfiltrates were concentrated to dryness using a rotary evaporator asabove, giving the title compound as a yellowish solid. Yield 2.14 g(90%). NMR complied with NMR of the product from step 3 in example 1.

Example 71-[7-(difluoromethoxy)spiro[1,3-benzodioxole-2,4′-tetrahydrothiopyran]-4-yl]-ethanone

Sodium hydroxide (301 g, 7.52 mol) was stirred with water (2.0 L), andthe resulting solution was cooled with an ice-water bath.1-(7-hydroxyspiro[1,3-benzodioxole-2,4′-tetrahydrothiopyran]-4-yl)ethanone(100.1 g, 0.3757 mol) and acetonitrile (1.0 L) were added. Diethylbromodifluorophosphonate (150.5 g, 0.5637 mol) was added slowly overapproximately 40 minutes at a temperature of 15-20° C. in the reactionmixture. Stirring was continued for another approximately two hours at15-20° C. The phases were separated.

Water (920 mL) was added slowly to the organic phase with stirring andthe resulting suspension was stirred at ambient temperature forapproximately 18 hours. The product was isolated by filtration, washedwith a 1:1 mixture of acetonitrile and water (120 mL), and dried invacuo at 50° C. with a bleed of air. Yield 108 g (91%). NMR compliedwith NMR of the product from step 3 in example 1.

Example 81-[7-(difluoromethoxy)spiro[1,3-benzodioxole-2,4′-tetrahydrothiopyran]-4-yl]-ethanone

To a mixture of potassium carbonate (1.45 g, 10.5 mmol) in DMF (8.2 mL)and water (3.6 mL) at a reaction temperature of 110° C. was slowly addeda solution of1-(7-hydroxyspiro[1,3-benzodioxole-2,4′-tetrahydrothiopyran]-4-yl)ethanone(2.0 g, 7.51 mmol) and sodium chlorodifluoro acetate (2.86 g, 18.8 mmol)in DMF (6.2 mL) over a period of 2-4 h. After completion of addition thereaction mixture was stirred for another 60 min. The reactiontemperature was then brought down to 70° C. where an aqueous 0.5M NaOHsolution (10 mL) was added to the reaction mixture. The obtainedreaction slurry was then slowly cooled down to 10-20° C. The product wasisolated by filtration, washed with water (40 mL), and dried undervacuum at 60° C. Yield 1.73 g (73%). NMR complied with NMR of theproduct from step (3) in Example 1.

Example 92-(3,5-dichloro-4-pyridyl)-1-[7-(difluoromethoxy)spiro[1,3-benzodioxole-2,4′-tetrahydrothiopyran]-4-yl]ethanone

Dimethyl formamide (128 mL) and tert-butanol (298 mL) were charged to asuitable reactor followed by addition of potassium tert-butoxide (81.4g, 726 mmol). The mixture was stirred until potassium tert-butoxide haddissolved.

A second reactor was charged with1-[7-(difluoromethoxy)spiro[1,3-benzodioxole-2,4′-tetrahydrothiopyran]-4-yl]ethanone(85.0 g, 269 mmol), 3,4,5-trichloropyridine (58.8 g, 322 mmol),dimethylformamide (76.5 mL) and tert-butanol (179 mL). The mixture wasstirred at 22-25° C., when the solution of potassium tert-butoxide indimethylformamide and tert-butanol was added slowly, keeping thetemperature of the reaction mixture <30° C. The reaction mixture wasstirred at 22-25° C. until the conversion was ≥98% as indicated by HPLC.

Water (340 mL) was added slowly to the reaction mixture keeping thetemperature <30° C. The reaction mixture was transferred to a separatoryfunnel and diluted with ethyl acetate (850 mL). The aqueous lower phasewas discarded. The organic phase was washed with an aqueous sodiumhydroxide solution (2M, 500 mL), and the aqueous lower phase wasdiscarded. The organic phase was washed with water (340 mL) and theaqueous lower phase was discarded. The organic phase was transferred toa suitable reactor and concentrated under reduced pressure (100 mbar) at50° C. (jacket temperature) until the temperature of the vapor reached39° C. Then ethanol (255 mL) was added and the slurry was heated toreflux (90° C.) and stirred for one hour. Then the solution was cooledslowly to 5° C. The product was isolated by filtration, transfer wasensured with a rinse of ethanol (20 mL). The product was washed withcold (5°) ethanol (150 mL) and dried in vacuo at 45-55° C. Yield 91.0 g(73.2%). ¹H NMR (600 MHz, Chloroform-d) δ 8.52 (s, 2H), 7.46 (d, J=8.9Hz, 1H), 6.80 (d, J=8.9 Hz, 1H), 6.73 (t, J=73.3 Hz, 1H), 4.59 (s, 2H),3.01-2.85 (m, 4H), 2.47-2.30 (m, 4H). HPLC: Purity: 97%.

Example 10 Preparation of1-(7-hydroxyspiro[1,3-benzodioxole-2,4′-tetrahydrothiopyran]-4-yl)ethenone

A suitable reaction vessel was flushed with nitrogen. The nitrogen flowwas temporary stopped and1-(7-methoxyspiro[1,3-benzodioxole-2,4′-tetrahydro¬thiopyran]-4-yl)ethenone(1.00 kg, 3.57 mol) was charged to the reaction vessel followed byethanol (2.5 L), sodium hydroxide (314 g, 7.85 mol, 2.2 eq), and1-dodecanethiol (1.66 kg, 8.2 mol, 2.3 eq). The reaction mixture washeated to refluxing conditions while agitated, and this temperature wasmaintained for 22-24 hours.

IPC (Ion Pair Chromatography) was prepared in ethanol for HPLC analysis(220 nm). If the starting material was present in less than 2 area %,the reaction mixture was cooled to 20-25° C.

Hereafter, water (5 L) was charged to the reaction mixture uponagitation. Toluene (1.5 L) was added subsequently, and the mixture wasagitated for at least 15 minutes.

The agitation was stopped and the phases were allowed to separate.

The aqueous phase was washed twice with toluene (2×1.5 L) Water (1 L)was added followed by addition of an aqueous hydrochloric acid solution(18%, 1.5-1.6 kg, 2.1-2.2 eq).

The precipitate was filtered off and washed twice with water (2×2 L),and with heptane (2 L). The moist solid was transferred to the reactionvessel, and heptane (5 L) was added. The slurry was agitated and heatedto refluxing conditions, with water being removed azeotropically.

The mixture was cooled to 20-25° C. and the solid was filtered off anddried in vacuum. Yield: 80-90%. NMR complied with NMR of the productfrom step (2a) in Example 1.

Preparation of1-[7-(difluoromethoxy)spiro[1,3-benzodioxole-2,4′-tetrahydrothiopyran]-4-yl]ethenone

Potassium carbonate (3.12 kg, 22.6 mol, 1.4 eq) and DMF (15.8 kg) wasadded to a suitable reaction vessel (#1). The suspension was agitated at20-25° C. and the vessel and mixture were flushed with nitrogen for atleast 1 hour at 20-25° C.

In a separate reaction vessel (#2) equipped with a nitrogen bubble tubewas placed1-(7-hydroxyspiro[1,3-benzodioxole-2,4′-tetrahydro-ithiopyran]-4-yl)ethenone(4.3 kg, 16.2 mol, 1 eq), sodium chlorodifluoro acetate (6.16 kg, 40.4mol, 2.5 eq), and DMF (12 kg). The suspension was agitated at 20-25° C.and the vessel and mixture were flushed with nitrogen for at least 1hour at 20-25° C.

The suspension in vessel (#1) was heated to 115° C. and the content ofvessel (#2) was transferred to vessel (#1) over the course of 7-8 h.

An IPC was prepared in acetonitrile for HPLC analysis (220 nm), with thecriterion for further progress being: <5 area % of1-(7-hydroxyspiro[1,3-benzodioxole-2,4′-tetrahydro-ithiopyran]4-yl)ethenone.

The reaction mixture was cooled to 20-25° C. and aqueous KOH solution(0.75 M, 18.8 kg) was added to the reaction.

The precipitate was filtered off and washed with KOH solution (0.75 M, 9kg) followed by water (86 kg).

The moist material was dissolved in DMF (16 kg) and heated to 40-45° C.MSA (methane sulfonic acid) (3.44 kg, 35.8 mol, 2.2 eq) was added whilemaintaining the temperature between 45-50° C.

An IPC was prepared in acetonitrile for HPLC analysis (272 nm), with thecriterion for further progress being: <4 area % of chemical byproduct offormula (IXb).

The reaction mixture was cooled to 35-40° C. and an aqueous KOH solution(3.25M, 18.7 kg) was added to the mixture. After complete addition, themixture was cooled to 20-25° C. The criterion for further progress was apH value of the solution of 10-12.

The solid was filtered off and washed with KOH solution (0.75 M, 9 kg)followed by water (86 kg). The solid was dried in vacuum at temperatureof 60° C. Yield: >85% (>93% purity). NMR complied with NMR of theproduct from step (3) in Example 1.

Alternatively, TFA can be used for work up instead of MSA. The moistmaterial after first isolation was dissolved in DMF (100 ml). TFA(trifluoroacetic acid) (13.4 g, 116.4 mmol, 1.5-3 eq) was added togetherwith water (21 mL), the reaction was performed at 60-70° C.

The reaction mixture was cooled to 44-50° C. and an aqueous NaOHsolution (1.25M, 140 mL) was added to the mixture. After completeaddition, the mixture was stirred for 1 h.

The solid was isolated by filtration and washed with 0.5M NaOH and thenwater (480 mL). The solid was dried in vacuum at temperature of 50° C.Yield: >90% (>94% purity). NMR complied with NMR of the product fromstep (3) in Example 1.

Preparation of 3,4,5-tricholoropyridine

Step 1: A stirred solution of 4-pyridinol (1.0 eq.) in acetonitrile(15.0 vol.) and water (0.1 vol.) was heated to 40° C. and then addedN-chloro succinamide (2.2 eq.) in portions at 40-55° C. The reactionmixture was stirred for 6-8 h at 45-55° C., the progress of reaction wasmonitored by HPLC. After completion of the reaction the reaction werecooled and stirred for 3-4 h. The solid was filtered and washed withacetonitrile (1×2.0 vol.) and water (5.0 vol+2.0 vol). The product wasdried in oven up to constant weight.

Step 2: To a stirred suspension of 3,5-dichloro-4-pyridinol (1.0 eq.) inacetonitrile (5.0 vol.) was added POCl₃ (2.0 eq.). The reaction mixturewas heated to 50-55° C. and stirred for 24 hours. The progress of thereaction was monitored by HPLC. After completion of reaction, themixture was cooled. Then reaction mixture was slowly poured into water(5.0 vol) at 2-10° C. The mixture was stirred for 20-30 minutes and pHwas adjusted to 9-10 with 50% NaOH_((aq)). The temperature was raised to25-30° C. and the mixture was extracted with n-heptane (1×18.0 vol.,2×10.0 vol.). The combined organic layers were washed with water(1×5.0vol.) and then added charcoal (15% w/w) and stirred for 1-2 hours.The organic phase was filtered through hyflo bed and the filter cake waswashed with heptane (2.0 vol). The collected organic phase wasconcentrated under vacuum at 40° C. or below until up to 1.0 volpresent. The mixture was cooled to 25-30° C. and water (2.0 vol) wasadded. The mixture was again concentrated under vacuum to remove moreheptane. The concentration was stopped when less than 2.0 vol present.Water (5.0 vol) was added and the mixture was stirred for 2-3 h. Thesolid was isolated by filtration and washed with water (2.0 vol). Driedin vacuum oven at 40-45° C. until constant weight. 1H NMR (600 MHz,Chloroform-d) δ 8.52 (s, 2H)

Preparation of2-(3,5-dichloro-4-pyridyl)-1-[7-(difluoromethoxy)spiro[1,3-benzodioxole-2,4′-tetrahydrothiopyran]-4-yl]ethanone

DMF (5 L) was added to a reaction vessel and subsequently, potassiumtert-butoxide (0.92 L, 0.8 mol, 2.6 eq) was added in portions uponefficient agitation. The mixture was agitated at 20-25° C. under inertatmosphere overnight.1-[7-(difluoromethoxy)spiro[1,3-benzodioxole-2,4′-tetrahydrothiopyran]-4-yl]ethenone(1 kg, 3.16 mol, 1 eq) and 3,4,5-tricholoropyridine (0.73 kg, 4.1 mol,1.3 eq) were added to a reaction vessel (#2) followed by DMF (4.5 L).The agitation was started at a rate that ensures good mixing of thereactants.

The solution of potassium tert-butoxide was added to vessel (#2).

When1-[7-(difluoromethoxy)spiro[1,3-benzodioxole-2,4′-tetrahydrothiopyran]-4-yl]ethenonewas <2%, the reaction mixture was cooled and added water (1 L) and ethylacetate (10 L)

Water (19 L) was added and the mixture was agitated. The agitation wasstopped, and the phases were allowed to separate. Temperature was keptat 35-45° C.

The lower aqueous phase was discarded. Ethyl acetate (5 L) was addedfollowed by water (20 L). The mixture was agitated, and after agitationthe phases were allowed to separate.

The lower aqueous phase was discarded. The organic phase was heated torefluxing conditions upon agitation. While at reflux, ethanol (15 L) wascharged to the mixture, at a rate which allows the refluxing conditionsto be maintained. The azeotropic solvent mixture was distilled off untilthe vapor temperature was 74-76° C.

The temperature of the mixture was cooled and the product was filteredoff and washed twice with cold ethanol (2×2.5 L).

The product was dried in vacuum at 40-50° C. Yield: 45-80%. NMR compliedwith NMR of the product from step (4) in Example 1.

Preparation of2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-[7-(difluoromethoxy)-1′,1′-dioxo-spiro[1,3-benzodioxole-2,4′-thiane]-4-yl]ethenone

In an reaction vessel was placed2-(3,5-dichloro-4-pyridyl)-1-[7-(difluoromethoxy)-spiro[1,3-benzodioxole-2,4′-tetrahydrothiopyran]-4-yl]ethanone(16.1 kg, 34.8 mol, 1 eq) and glacial acetic acid (33.8 kg). Thesuspension was cooled to 15-20° C. Peracetic acid (36-40%, 20.5 kg,104.7 mol, 3.01 eq) was added to the mixture in portions. The mixturewas heated to 60° C. and agitated for 12-24 hours.

An IPC was prepared in acetonitrile for HPLC analysis (220 nm). Thereaction was done, when2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-[7-(difluoromethoxy)-1′,1′-dioxo-spiro[1,3-benzodioxole-2,4′-thiane]-4-yl]ethanone >98.5area %.

Acetic acid (36 kg) and sodium metabisulfite (2.415 kg, 12.7, 0.36 eq)was added to reaction mixture. The mixture was heated to 40-45° C. forat least 3 hours.

Acetic acid was removed by evaporation in vacuum and ethanol (386 L) wasthen added upon agitation followed by water (16 L).

The title compound (141 g, Form E) was added to the mixture, and themixture was then heated to reflux.

The solid was filtered off, washed with ethanol (39 L), and dried invacuum at 50° C. Yield: 80-90%). NMR complied with NMR of the productfrom step (5) in Example 1.

The X-ray powder diffraction pattern appears from Graph 1.

1. A method for the preparation of a compound of formula (I)

wherein R₁ is selected from CHF₂ and CF₃, Q is selected from chloro,bromo and fluoro, comprising: (1) reacting a compound of formula (II)

wherein R₂ is selected from hydrogen, C₁₋₆-alkyl and arylalkyl, R₂₁ isselected from hydrogen and C(O)R₂₂, and R₂₂ is selected from hydrogenand C₁₋₆-alkyl; with a compound of formula (III)

in the presence of an acid catalyst in the form of a clay or a zeolite,to form a compound of formula (IV)

wherein R₂ and R₂₁ is as defined above; (2a) reacting the compound offormula (IV)

wherein R₂ and R₂₁ is as defined above with an aliphatic or aromaticthiol in the presence of a metal hydroxide in a suitable solvent toobtain a compound of formula (VI)

wherein R₂₁ is defined above; (3′) reacting the compound of formula(VI),

wherein R₂₁ is defined above, by addition of a solution of the compoundof formula (VI) and sodium chlorodifluoro acetate inN,N-dimethylformamide (DMF) to a pre-heated mixture of DMF, water andpotassium carbonate to obtain the compound of formula (IX),

wherein R₁ and R₂₁ are as defined above; (4) reacting the compound offormula (IX) with a pyridine compound of formula (X)

wherein Q is as defined above and Q_(X) is selected from chloro, bromo,fluoro, and iodo, to form a compound of formula (XI);

wherein R₁ and Q are as defined above; and (5) oxidizing the resultingcompound of formula (XI) to prepare the compound of formula (I).
 2. Themethod according to claim 1 wherein the metal hydroxide in (2a) is NaOH.3. The method according to claim 1 wherein the reaction in (2a) isperformed using NaOH, 1-dodecanethiol, and ethanol.
 4. The methodaccording to claim 1 wherein the reaction in (2a) is performed usingNaOH, 1-dodecanethiol, and 1-propanol.
 5. The method according to claim1, wherein in (3′) the compound of formula (IX) is isolated by the useof trifluoracetic acid (TFA) or methanesulfonic acid (MSA) in DMF, atelevated temperature and subsequent removal by treatment with an aqueousbase.
 6. The method according to claim 5, wherein the aqueous base ischosen from KOH and NaOH.
 7. The method according to claim 1, whereinthe reaction in (4) is conducted in a solvent of DMF/tBuOH and usingtert-BuOK as base.
 8. The method according to claim 7 wherein thesolvent of DMF/tBuOH is a 30/70 v/v mixture.
 9. The method according toclaim 1 wherein in (5) the compound of formula (I) is crystalizeddirectly from the concentrated reaction mixture.
 10. The methodaccording to claim 1 wherein R₁ is CHF₂.
 11. The method according toclaim 1 wherein each Q and each Q_(x) are chloro.
 12. The methodaccording to claim 1 wherein in (1) the acid catalyst is the silicatematerial Montmorillonite K₁₀.
 13. (canceled)
 14. A method for preparinga compound of formula (I)

wherein R₁ in formula (I) is selected from CHF₂ and CF₃, and Q informula (I) is selected from chloro, bromo, and fluoro, comprisingreacting a compound of formula (IV)

with an aliphatic or aromatic thiol in the presence of a metal hydroxidein a suitable solvent to obtain a compound of formula (VI)

wherein R₂ is selected from hydrogen, C₁₋₆-alkyl and arylalkyl; R₂₁ isselected from hydrogen and C(O)R₂₂; and R₂₂ is selected from hydrogenand C₁₋₆-alkyl.
 15. The method according to claim 14 wherein the metalhydroxide is NaOH.
 16. The method according to claim 14 wherein thereaction is performed using NaOH, 1-dodecanethiol, and ethanol.
 17. Themethod according to claim 14 wherein the reaction is performed usingNaOH, 1-dodecanethiol, and 1-propanol.
 18. A method for preparing acompound of formula (I)

wherein R₁ in formula (I) is selected from CHF₂ and CF₃, and Q informula (I) is selected from chloro, bromo and fluoro, comprisingreacting a compound of formula (VI),

by addition of a solution of the compound of formula (VI) and sodiumchlorodifluoro acetate in N,N-dimethylformamide (DMF) to a pre-heatedmixture of DMF, water and potassium carbonate to obtain the compound offormula (IX),

wherein R₂₁ is selected from hydrogen and C(O)R₂₂; and R₂₂ is selectedfrom hydrogen and C₁₋₆-alkyl.
 19. The method according to claim 18,wherein the compound of formula (IX) is isolated by the use of TFA orMSA in DMF, at elevated temperature and subsequent removal by treatmentwith an aqueous KOH base.
 20. The method according to claim 19, whereinthe aqueous base is chosen from NaOH and KOH.
 21. A method for preparinga compound of formula (I)

wherein R₁ in formula (I) is selected from CHF₂ and CF₃, and Q informula (I) is selected from chloro, bromo and fluoro, comprisingreacting a compound of formula (IX)

wherein R₂₁ is selected from hydrogen and C(O)R₂₂, and R₂₂ is selectedfrom hydrogen and C₁₋₆-alkyl, with a pyridine compound of formula (X)

wherein Q_(X) is selected from chloro, bromo, fluoro, and iodo, to forma compound of formula (XI)

wherein the reaction is conducted in a solvent of DMF/tBuOH and a baseof tert-BuOK.
 22. The method according to claim 21 wherein the solventof DMF/tBuOH is a 30/70 v/v mixture.
 23. A method for preparing acompound of formula (I)

wherein R₁ in formula (I) is selected from CHF₂ and CF₃, and Q informula (I) is selected from chloro, bromo and fluoro, comprisingoxidizing a compound of formula (XI)


24. A crystalline form (E) of2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-[7-(difluoromethoxy)-1′,1′-dioxo-spiro[1,3-benzodioxole-2,4′-thiane]-4-yl]ethenonehaving an X-ray powder diffraction pattern as in FIG. 1.